1. Field of the Invention
This invention relates to methods of treating oropharyngeal mucositis and other oral and nasal mucositis by oral or nasal administration of glutamine.
2. Description of the Related Art
Mucositis is a common limiting toxicity of cancer chemotherapy. While the term mucositis refers to inflammation of a mucous membrane, this term is often used synonymously with stomatitis to refer to inflammation of the oral mucosa. The strict definitions of stomatitis (inflammation of the oral mucosa), enteritis (inflammation of the intestines), and mucositis (inflammation of mucous membranes including any region of the alimentary canal) will be used to avoid confusion.
Although often a result of the bolus administration of anti-neoplastic agents, gut toxicity may be even more common when some agents are given by continuous infusion. There has been increasing interest in the administration of cancer chemotherapy by continuous infusion, since continuous infusion chemotherapy results in exposure of the tumor to cytotoxic drugs for a more prolonged period of time than does bolus administration, and may therefore be more efficacious than bolus chemotherapy for tumors with low growth fractions. However, it is clear that continuous infusion chemotherapy may have a toxicity profile different from bolus drug administration and for some drugs may be associated with more mucositis. In particular, the continuous infusion of doxorubicin is associated with less cardiotoxicity than bolus administration, but often mucositis becomes the dose limiting toxicity. Similarly, the dose-limiting toxicity of 5-fluorouracil given by bolus administration is usually leukopenia, while gut toxicity, including stomatitis and esophagitis, can become a more important toxicity when the drug is given by continuous infusion over more prolonged periods or when combined with folinic acid (Leucovorin.RTM.). Gastrointestinal toxicity manifested by diarrhea, felt to be due to enteritis, is the major limiting toxicity of infusional FUdR.
The mechanism of chemotherapy-induced mucositis may be multifactorial. Presumably, chemotherapy damages the rapidly dividing immature intestinal crypt cells and more superficial immature mucosal cells in the oropharynx. In addition to this direct damage, it is possible that, as the mature epithelial cells are sloughed, damaged immature cells are exposed to pancreatic and biliary secretions resulting in further intestinal damage. The gut is among the largest repositories of lymphoid tissue in the body and the gut-associated lymphoid tissue has been termed GALT (Enteral Nutr. 14: 109S-113S, 1990). The effects of chemotherapy on this lymphoid tissue may result in an additional disruption to the gut mucosal integrity, in addition to the direct effects of chemotherapy on the enterocytes. Other factors may also be involved; in normal individuals there is a constant and closely regulated flow of energy, mediated by various metabolites, among different tissues in the body (Adv. Enzymology 53:202-231, 1982). Chemotherapy may directly, or indirectly via decreasing nutrient intake, alter the production by another body compartment of a metabolite necessary for the gut, for example glutamine (see below). Such an effect can be seen during catabolic illness when the plasma glutamine concentration often falls. Although perhaps more the result, rather than the cause, of mucositis, the phenomenon of bacterial translocation across a malfunctioning gut epithelium may also play a role in the gut-related toxicity of chemotherapy and radiotherapy.
Glutamine is the most abundant amino acid in the blood and in the total body amino acid pool, and recently there has been much interest in its role in nutrition. Glutamine serves many important functions: it is a nitrogen donor for various synthetic pathways; it is a precursor for nucleic acid and nucleotide synthesis; it plays an important role in acid-base balance as a substrate for renal ammoniagenesis; and it is the major precursor of the important neurotransmitters glutamate, an excitatory amino acid, and gamma-aminobutyric acid, an inhibitory metabolite. In addition, it is an important energy source for the immune system, especially lymphocytes and macrophages.
Glutamine is a "non-essential" amino acid in that it can be synthesized by most tissues. Skeletal muscle is probably the major source of glutamine synthesis in vivo, although this has not been quantitated. However, while the metabolism of some tissues, such as skeletal muscle and brain, yield a net synthesis and export of glutamine, cells of other tissues utilize glutamine both as a nitrogen source and also as an energy source.
Glutamine appears to be the major energy source for intestinal epithelium (Adv. Enzymology 53:202-231, 1982). The small intestine utilizes large quanities of glutamine, extracting 20-30% of the circulating glutamine in the post-absorbant state. It is noteworthy that the presence of glutamine or glutamate in the gut lumen decreases the extraction of glutamine by the intestine from arterial blood, and that most dietary glutamine is metabolized by the gut directly, demonstrating that glutamine in the gut can be utilized by the intestine without first making it available to the rest of the body through the circulation. In addition to being a primary fuel for gut enterocytes, glutamine may be essential for gut epithelium. For example, parenteral glutamine supplementation of total parenteral hyperalimentation decreases the villous atrophy associated with exclusive feeding via total parenteral nutrition. In vitro studies have shown that fetal mouse intestine is unable to differentiate to its mature phenotype unless glutamine is added to the tissue culture medium.
It has been theorized that elemental diets that provide nitrogen as amino acids and carbohydrate as simple sugars, with added vitamins and minerals, might decrease the gastrointestinal toxicity of chemotherapy by providing readily absorbable nutrients to the enterocytes directly through the intestinal lumen. In addition, they might decrease biliary and pancreatic secretions which could further damage the mucosa. Despite these theoretical benefits, elemental diets increased the toxicity of animals given methotrexate or 5-FU (J. Parenter. Enteral Nutr. 12:325-331, 1988). However, supplementation of an elemental diet with glutamine may protect the gut from both radiation and some chemotherapeutic agents. Studies in rats treated with methotrexate demonstrated that glutamine supplementation of an elemental diet resulted in less weight loss, increased mucosal weight of the jejunum and colon, longer survival, less mortality, and a lower incidence of bacteremia. A similar benefit of glutamine supplementation of an elemental diet was seen in another study of rats treated with methotrexate. Klimberg, et al treated rats with elemental diets enriched in either glutamine or glycine before administering abdominal radiotherapy. Rats in the glutamine group had a more normal mucosal structure and a higher survival rate than rats in the glycine enriched group (Cancer 66:62-68, 1990). Both animal and human studies suggest that enteral nutrition results in more normal gut function than parenteral nutrition, and in the setting of major abdominal trauma, enteral nutrition appears to reduce the incidence of septic complications compared with parenteral nutrition. Animal studies suggest that enteral glutamine supplementation yields a better survival rate than parenteral supplementation, when administered after methotrexate (Burke et al, J. Parenter. Enteral Nutr. 14(1) p. 8S, 1990).
L-glutamine has been administered safely to humans both orally and intravenously. In fasting, healthy, adult males an oral dose of 0.3 g/kg resulted in a transient increase in blood glutamine, peaking at .about.1300 .mu.M at .about.30-45 min and returning to baseline (.about.680 .mu.M) by 4 hours, with no evidence of clinical toxicity or generation of measurable toxic metabolites (ammonia or glutamate) (J. Parenter. Enteral Nutr. 14:137S-146S, 1990). An oral dose of 0.1 g/kg resulted in a peak glutamine concentration of .about.1000 .mu.M. In another study, the ingestion over 4 minutes of a mixture of amino acids (0.8 g/kg body weight; .about.0.064 g/kg of glutamine) simulating the amino acid content of an animal protein meal, resulted in a peak increase of the arterial glutamine from .about.524 .mu.M to .about.558 .mu.M at 45 min, returning to baseline by 1 hour (Am. J. Clin. Nutr. 48:72-83, 1988). Similarly, the addition of 0.57 g/kg/day of L-glutamine to parenteral nutrition solutions administered for 5 days to normal subjects was well tolerated (J. Parenter. Enteral Nutr. 14:137S-146S, 1990). In this study, the plasma glutamine was 40% higher (.about.975 vs .about.700 .mu.M) in the glutamine supplemented group after 1 week of total parenteral nutrition. Such studies are relevant since, although one might tend to view glutamine as a normal component of the diet and thus likely harmless, glutamine and its two major metabolic products, ammonia and glutamate, can cross the blood brain barrier and potentially lead to altered central nervous system function.
Forty-five adults undergoing allogeneic bone marrow transplantation for hematologic malignancies were randomized in a double blind manner to parenteral nutrition with or without parenteral glutamine supplementation. Significant benefits were seen in the glutamine treatment group including better nitrogen balance, fewer episodes of clinical infections, and a shorter median hospitalization (Ann. Int. Med. 116:821-828, 1992). In this study, with a high dosage of intravenous glutamine, no difference in the severity of oral mucositis (stomatitis) was seen.
U.S. Pat. No. 5,039,704 to Wilmore et al describes the parenteral and enteral administration (defined as stomach and lower gastrointestinal tract) of glutamine to treat catabolic dysfunctions. In the catabolic dysfunctions described, glutamine is derived through the breakdown of muscle tissue. In spite of this source from muscle, intestinal mucosal cell demand exceeds supply. Wilmore et al supplies glutamine through a feeding tube into the small intestine at a rate of at least about 21 grams per day for a 70 kg patient.
The art described in this section is not intended to constitute an admission that any patent, publication or other information referred to herein is "prior art" with respect to this invention, unless specifically designated as such. In addition, this section should not be construed to mean that a search has been made or that no other pertinent information as defined in 37 C.F.R. .sctn. 1.56(a) exists.